title: Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma.
abstract: BACKGROUND
  The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting.
  
  
  METHODS
  We here present the first seven patients treated with a dendritic cell (DC)-based vaccine targeting CSCs in a solid tumor. Brain tumor biopsies were dissociated into single-cell suspensions, and autologous CSCs were expanded in vitro as tumorspheres. From these, CSC-mRNA was amplified and transfected into monocyte-derived autologous DCs. The DCs were aliquoted to 9-18 vaccines containing 10(7) cells each. These vaccines were injected intradermally at specified intervals after the patients had received a standard 6-week course of post-operative radio-chemotherapy. The study was registered with the ClinicalTrials.gov identifier NCT00846456.
  
  
  RESULTS
  Autologous CSC cultures were established from ten out of eleven tumors. High-quality RNA was isolated, and mRNA was amplified in all cases. Seven patients were able to be weaned from corticosteroids to receive DC immunotherapy. An immune response induced by vaccination was identified in all seven patients. No patients developed adverse autoimmune events or other side effects. Compared to matched controls, progression-free survival was 2.9 times longer in vaccinated patients (median 694 vs. 236 days, p = 0.0018, log-rank test).
  
  
  CONCLUSIONS
  These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival.
authors.affiliation: Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research, University of Oslo, Oslo, Norway. e.o.vik-mo@medisin.uio.no
authors.forename: Einar Osland
authors.initials: EO
authors.lastname: Vik-Mo
authors.forename: Marta
authors.initials: M
authors.lastname: Nyakas
authors.forename: Birthe Viftrup
authors.initials: BV
authors.lastname: Mikkelsen
authors.forename: Morten Carstens
authors.initials: MC
authors.lastname: Moe
authors.forename: Paulina
authors.initials: P
authors.lastname: Due-Tønnesen
authors.forename: Else Marit Inderberg
authors.initials: EM
authors.lastname: Suso
authors.forename: Stein
authors.initials: S
authors.lastname: Sæbøe-Larssen
authors.forename: Cecilie
authors.initials: C
authors.lastname: Sandberg
authors.forename: Jan E
authors.initials: JE
authors.lastname: Brinchmann
authors.forename: Eirik
authors.initials: E
authors.lastname: Helseth
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Rasmussen
authors.forename: Knut
authors.initials: K
authors.lastname: Lote
authors.forename: Steinar
authors.initials: S
authors.lastname: Aamdal
authors.forename: Gustav
authors.initials: G
authors.lastname: Gaudernack
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kvalheim
authors.forename: Iver A
authors.initials: IA
authors.lastname: Langmoen
mesh_terms: D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D019098:Telomerase / Q000235:genetics / Q000276:immunology; D014162:Transfection
chemical_list: D019496:Cancer Vaccines; D012333:RNA, Messenger; C509186:TERT protein, human; D019098:Telomerase